Whereas aniline m- and p-toluidines are not carcinogenic, o- toluidine is carcinogenic. Also ortho-methyl substitution in 2- naphthylamine or 4-biphenylamine enhances the carcinogenicity and, depending on the experimental protocols, affects diverse target tissues. Certain of these chemicals are important industrial products. There is no information on their mode of action or rational explanation for their target specificities. It is, therefore, timely and useful to develop a systematic program of fundamental research on the mechanism of this particular class of compounds with some emphasis on the elucidation of the reasons why o- methylaminoaryl derivatives possess such biological effects, by studying their metabolism in vivo and in vitro. We are planning to develop syntheses of the labeled carcinogens by efficient methods. We will also synthesize possible metabolites which can be presumed to be present on the basis of our extensive background in metabolism studies of chemical carcinogens. The existence of these suspected metabolites will be determined in various rodent animal models, with emphasis on a comparison between rats and hamsters, species which show divergent response to some of these carcinogens. Additionally, long-term plans include a determination of the interaction of these chemicals with cellular macromolecules in target tissues and controls. It is hoped that an understanding of the metabolic pathways and interaction of these chemicals will help to elucidate the mechanism of action and provide a lead to rational preventive measures.